Kaagaard et al.

BMC Infectious Diseases (2023) 23:327 BMC Infectious Diseases

https://doi.org/10.1186/s12879-023-08311-y

RESEARCH Open Access

Frequency of pleural effusion in dengue

patients by severity, age and imaging
modality: a systematic review and meta-
analysis
Molly D. Kaagaard1,2*, Luan Oliveira Matos1, Marliton V. P. Evangelista1, Alma Wegener1,2, Anna Engell Holm1,2,
Lasse S. Vestergaard3, Suiane C. N. Do Valle1, Odilson M. Silvestre4, Marcus Vinícius Guimarães Lacerda5,6,
Rodrigo Medeiros de Souza1, Flavia Barreto dos Santos7, Tor Biering-Sørensen2,8 and Philip Brainin1,2,9

Abstract
Background Identification of pleural effusion (PE) in dengue infection is an objective measure of plasma leakage and
may predict disease progression. However, no studies have systematically assessed the frequency of PE in patients
with dengue, and whether this differs across age and imaging modality.
Methods We searched Pubmed, Embase Web of Science and Lilacs (period 1900–2021) for studies reporting on PE in
dengue patients (hospitalized and outpatient). We defined PE as fluid in the thoracic cavity detected by any imaging
test. The study was registered in PROSPERO (CRD42021228862). Complicated dengue was defined as hemorrhagic
fever, dengue shock syndrome or severe dengue.
Results The search identified 2,157 studies of which 85 studies were eligible for inclusion. The studies (n = 31
children, n = 10 adults, n = 44 mixed age) involved 12,800 patients (30% complicated dengue). The overall frequency
of PE was 33% [95%CI: 29 to 37%] and the rate of PE increased significantly with disease severity (P = 0.001) such that
in complicated vs. uncomplicated dengue the frequencies were 48% and 17% (P < 0.001). When assessing all studies,
PE occurred significantly more often in children compared to adults (43% vs. 13%, P = 0.002) and lung ultrasound
more frequently detected PE than conventional chest X-ray (P = 0.023).
Conclusions We found that 1/3 of dengue patients presented with PE and the frequency increased with severity and
younger age. Importantly, lung ultrasound demonstrated the highest rate of detection. Our findings suggest that PE
is a relatively common finding in dengue and that bedside imaging tools, such as lung ultrasound, potentially may
enhance detection.
Keywords Dengue fever, Pleural effusion, Ultrasound, Plasma leakage

*Correspondence:
Molly D. Kaagaard
mollykaagaard@gmail.com
Full list of author information is available at the end of the article

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Kaagaard et al. BMC Infectious Diseases (2023) 23:327 Page 2 of 9

Background Exclusion criteria were the following: studies in other

Dengue is a viral, vector-borne disease present in over languages than English, French, Spanish, or Portuguese,
100 countries in the tropics and subtropics, affecting known concomitant infection (such as malaria, COVID-
more than 105 million people each year [1]. The clinical 19 or other pulmonary infections), known pulmonary
presentation ranges from asymptomatic disease, over disease or heart failure at baseline, known heart/lung/
mild infection with fever and joint pain, to severe dengue kidney transplant, recent chest trauma or surgery (< 4
with plasma leakage and bleeding, potentially leading to weeks ago) or catheter attached to the thorax.
shock and death. In 1997 the World Health Organization
(WHO) categorized the clinical presentation of dengue Search and review
infection as either dengue fever, dengue hemorrhagic We searched PubMed, Embase, Web of Science and
fever or dengue shock syndrome [2]. This was changed in Lilacs from 1900 to 2021 using a broad search string
2009 to three novel categories: dengue without warning including “Dengue virus” OR “Dengue infection” OR
signs, dengue with warning signs and severe dengue [3]. “DENV” AND “Pleural effusion” OR “Pulmonary edema”
While the 1997 classification recognized plasma leakage AND “Diagnostic imaging” OR “Ultrasound”. The full
as a key parameter of dengue severity, the 2009 defini- search string is presented in Supplemental Table 1. Fur-
tion emphasized individual organ dysfunction as more thermore, we examined bibliographies of included and
important, and only plasma leakage leading to shock or excluded studies. Two independent reviewers (MDK,
respiratory distress is classified as a severe case [4]. Note- MVPE) performed the literature search and screened
worthy, many researchers and clinicians continue to use titles and abstracts to identify potentially eligible articles.
the old classification [5], arguing that it is more reliable, The full-text articles of these were screened by MDK and
and that delayed identification of plasma leakage is a PB, and finally included or excluded. Finally, decisions
common cause of dengue mortality [6]. Indeed, a recent of the reviewers were compared, and disagreement was
meta-analysis showed that clinical signs of plasma leak- resolved by consensus.
age was a strong predictor of progression to severe den-
gue and that timely identification may lead to improved Data collection
management [7]. MDK and PB extracted data from the included articles,
Pleural effusion (PE) is a common manifestation of which involved country, year, sample size, baseline char-
plasma leakage in dengue [8] and is diagnosed by imag- acteristics (sex, age, inpatient/outpatient), diagnostic
ing diagnostic tests. As of today, only small-scale studies test, clinical complications, serotypes, disease severity
have reported sporadically on PE in dengue which has and mortality. Children were defined as ≤ 17 years old
been in the range of 2–100% [9, 10]. However, no study and disease severity was assessed using the classifica-
has systematically evaluated the frequency of PE in den- tion provided in the study (either WHO’s 1997 or 2009
gue and therefore it remains unknown to what extent algorithm). For the purpose of this study, we stratified
clinicians can use PE as a marker of disease severity. The the population into two severity groups: complicated
aim of this study was to determine the frequency of PE in and uncomplicated dengue. We defined complicated
dengue across disease severity, age groups and evaluate dengue as dengue hemorrhagic fever or dengue shock
whether certain imaging diagnostic tests would enhance syndrome (1997 classification) and severe dengue (2009
detection of PE. classification) (Supplemental Fig. 1). All other cases of
dengue were classified as uncomplicated. For studies
Methods that included patients with mixed dengue severity, we
We included full-text clinical studies according to the sought to extract individual patient data when possible.
Preferred Reporting Items for Systematic Reviews and Moreover, we extracted information about the imaging
Meta-Analyses (PRISMA) [11]. The study was registered methods for detection of PE. If studies assessed PE sev-
in PROSPERO (registration No.: CRD42021228862) [12]. eral times during hospitalization, we used the imaging
test performed closest to defervescence where the risk of
Criteria plasma leakage is considered highest [13].
We assessed studies of children and adults with a posi-
tive test for dengue determined by rapid diagnostic tests Bias assessment
and Enzyme-Linked Immunosorbent Assay (ELISA) Quality of included studies was assessed by MDK and PB,
showing presence of NS1 antigen, IgM or IgG, reverse using the NIHLBI tool [14] for observational cohort and
transcription polymerase chain reaction, or hemaggluti- cross-sectional studies (Supplemental Table 2).
nation inhibition. Studies were included if they reported
PE assessed by a paraclinical imaging diagnostic: chest
X-ray (CXR), ultrasound or computed tomography (CT).
Kaagaard et al. BMC Infectious Diseases (2023) 23:327 Page 3 of 9

Statistics Results
Frequencies of PE were extracted from individual stud- The literature search and bibliography screening yielded
ies and afterwards we applied a random-effects model 2,157 studies. Of these, 1,786 (82%) were excluded on
to assess the pooled frequency of PE across studies. the basis of title and abstract, and 26 studies could not
We used the metaprop command in STATA [15] and be retrieved in full text (Fig. 1). We assessed 345 studies
assessed pooled estimates in four study categories: (i) in full text and 85 were included (published from 1991 to
Across all studies, (ii) by age group (children vs. adults), 2020; Supplemental Table 3) [4, 9, 10, 17–98].
(iii) by severity (complicated vs. uncomplicated) and (iv) We found an overall acceptable degree of bias among
by imaging diagnostic test. Heterogeneity was assessed the included studies, where 49% were rated ‘good’ using
using the I2 value and forest plots were constructed to the applied tool, and 42% were rated ‘fair’.
display frequency estimates. P-values for heterogeneity The studies more often assessed dengue severity using
were considered significant when below 0.05. Frequen- the 1997 WHO classification (n = 48) than the 2009 clas-
cies of PE across subgroups, such as CXR vs. ultrasound sification (n = 20), and 17 studies did not specify the clas-
vs. CT, were compared using Cuzick’s non-parametric sification. Three studies were published before 1997 [47,
test for trend [16], whereas individual subgroups were 50, 69]. The studies included 12,800 patients (49% male,
compared using Wilcoxon rank sum test. Meta regres- mean age 24 years) and a majority had mixed adults
sion models were conducted to investigate whether geo- and children (n = 34), followed by studies of children
graphical region and classification algorithm influenced (n = 31), adults (n = 10) and unspecified age (n = 10). Most
the frequency of PE. We considered P-values < 0.05 as sig- included hospitalized patients (n = 66), of which four
nificant. Statistical analyses were performed with STATA were conducted in intensive care units, three were from
(version 13.1, College Station, TX). emergency departments and eight had a mix of hospital-
ized and ambulatory patients. Geographically, a major-
ity of studies were conducted in South-East Asia (n = 68)
(Supplemental Fig. 2) and most used ELISA for IgM/IgG
seroconversion to diagnose dengue (n = 47) (Supplemen-
tal Table 3). Few studies reported on dengue and associ-
ated clinical complications (Supplemental Table 4) and
few (n = 13) had data on serotype (Supplemental Table 5)
for which there was no clear pattern associated with PE.

Pooled frequency of pleural effusion

The meta-analysis of all studies yielded a pooled PE fre-
quency of 33% [95%CI 29 to 37%] (Fig. 2) and hetero-
geneity was considered high with an I2 of 98%, P < 0.01.
Among three studies assessing mortality, survivors had
lower frequency of PE (14% [95% CI -24 to 52%]) than
those who died (46% [95%CI -13 to 104%]). A meta-
regression showed that the geographical region in which
studies were conducted did not affect occurrence of PE
(P = 0.32). By contrast, classification was associated with
PE such that the highest frequency occurred in studies
using the 1997 classification (P = 0.004).

Pleural effusion by severity

Uncomplicated: Studies of uncomplicated dengue (n = 26)
had the lowest number of patients (n = 2,431 patients, age
range 0–93 years), and they displayed the lowest pooled
frequency of PE (17% [95%CI 12 to 22%]). Mixed: Stud-
ies of mixed dengue severity (n = 28) had more patients
(n = 5,764 patients; age range 0–93 years, 61% male,) and
the frequency of PE was lower (29% [95%CI 22 to 35%]).
Complicated: In studies of complicated dengue (n = 47
Fig. 1 Flowchart of inclusion and exclusion studies, n = 2,978 patients, age range 0–92 years, 49%
Overview of search results and reasons for exclusion
Kaagaard et al. BMC Infectious Diseases (2023) 23:327 Page 4 of 9

P < 0.01). Studies using the 1997 WHO classification

reported higher frequencies of PE (38% [95%CI 32 to
45%]) compared to studies using the 2009 classification
(17% [95%CI 14 to 21%]) (P = 0.003), thereby confirming
the findings from the metaregression analysis.

Pleural effusion by age group

The frequency of PE was significantly higher in children
compared to adults (43% vs. 13%, P = 0.002, Table 1).
Specifically for children, PE occurred significantly more
in complicated vs. uncomplicated disease (58% vs. 12%,
P < 0.001), while this was not the case among adults
(P = 0.44). The analyses displayed high heterogeneity with
I2 values ranging from 96 to 99%, P < 0.01.

Pleural effusion by imaging test

Diagnostic tests to identify PE involved ultrasound
(n = 44), CXR (n = 37), combined ultrasound and CXR
(n = 10) and CT (n = 2). Studies using ultrasound reported
a pooled frequency of PE of 38% [95%CI 31 to 46%], CXR
studies 28% [95%CI 22 to 34%] and mixed ultrasound/
CXR 26% [95%CI 19 to 33%]. Two studies using CT
reported the highest frequency of PE: 59% [95%CI 47 to
71%]. Frequency of PE varied significantly across imaging
modalities (P trend = 0.010; Table 1), such that CT and
ultrasound more often identified PE compared to CXR.
Ultrasound studies also detected more PE compared to
CXR (P = 0.023) when excluding CT and mixed studies.

Discussion
Plasma leakage is associated with mortality in dengue
infection [7] and the most common manifestation is PE
[2]. Hence, early recognition of PE is useful for risk strati-
fication and may facilitate rapid initiation of treatment.
In this meta-analysis we showed that PE occurred in up
to one third of all dengue cases, increased with sever-
ity and more often appeared in children. Furthermore,
we found that ultrasound detected higher rates of PE as
compared to CXR.
Present studies of plasma leakage in dengue are of het-
erogenous nature, observational and contain large differ-
ences in their estimates of PE. In two ultrasound studies
from India, Venkata et al [90] reported a PE frequency
of 5%, whereas Pothapregada et al [68] identified PE in
Fig. 2 Pooled frequency of PE 89%. Although the two studies share similar characteris-
Meta-analysis of PE based on all included studies tics (imaging test, population, region), they indicate great
variation in the reporting of an important complication
males) the pooled frequency of PE was 48% [95%CI 38 to to dengue. A recent meta-analysis found that PE and
59%]. ascites were predictors of progression to severe dengue
The frequency of PE increased with severity (P [7], which is comparable to our findings, where the fre-
trend = 0.001, Table 1) and patients with complicated quency of PE increased with dengue severity. However,
infection had significantly higher rate of PE compared the fact that PE was present in nearly 20% of patients
to uncomplicated dengue (48% vs. 17%, P < 0.001). Het- with uncomplicated dengue – and in 33% of all cases
erogeneity in these analyses was high (I2 from 96 to 99%, – may question its use as a prognostic factor. Severe
Kaagaard et al. BMC Infectious Diseases (2023) 23:327 Page 5 of 9

Table 1 Summary table of PE frequencies by severity, age group and imaging modality
Category Mean age, Children, Male, % Hospital- Secondary Ultrasound, Frequency of PE* Hetero-
years (range) n(%) ized, n(%) infection, % n(%) geneity
(I2)
Severity P-trend <0.001
Uncomplicated 12 (8 to 36) 13 (50%) - 25 (96%) 52 11 (42%) 17% [95%CI 12 to 96%
22%]
References: [10, 17, 20, 30, 32, 39, 43, 49, 53, 56, 58, 65, 67, 71, 74–76, 98]
Mixed 28 (8 to 34) 10 (36%) 59 23 (82%) 55 13 (46%) 29% [95%CI 22 to 99%
35%]
References: [9, 18, 21, 23, 25, 27, 31, 33, 34, 36, 37, 42, 44, 46, 48, 52, 55, 57, 63, 68, 72, 81–83, 85, 89–91]
Complicated 10 (8 to 32) 23 (49%) 53 44 (94%) 82 18 (38%) 48% [95%CI 38 to 98%
59%]
References: [10, 17, 19, 20, 28–30, 32, 34, 39, 41, 43, 45, 47, 49–51, 53, 56, 58, 62, 64–67, 69–71, 73–77, 79, 80, 84, 86–88, 93, 95–98]
Age group P-trend = 0.005
Children 8 (8 to 10) - 52 42 (89%) 82 19 (40%) 43% [95%CI 34 to 98%
51%]
References: [10, 19, 20, 24, 25, 28, 29, 31, 32, 46–50, 62, 66–69, 71, 74, 75, 77, 80, 82–85, 87, 90, 91, 98]
Mixed 32 (29 to 37) - 64 36 (88%) 42 23 (56%) 39% [95%CI 29 to 99%
49%]
References: [9, 17, 18, 22, 27, 30, 33–37, 40, 43, 45, 51, 55, 56, 59, 60, 63, 64, 70, 72, 73, 76, 78, 79, 81, 88, 93, 95, 97]
Adults 41 (32 to 50) - 54 11 (85%) 66 8 (62%) 13% [95%CI 9 to 96%
17%]
References: [21, 24, 26, 38, 42, 52–54, 61, 65, 94]
Imaging P-trend = 0.010
Ultrasound 28 (10 to 36) 14 (32%) 61 35 (80%) 47 - 38% [95%CI 31 to 99%
46%]
References: [4, 9, 17, 20–22, 24, 34, 35, 37–40, 51, 54–56, 59–65, 68, 69, 72–75, 78, 80, 81, 83–85, 90–92, 94, 95, 97, 98]
Chest X-ray 8 (8 to 26) 19 (51%) 60 34 (92%) 81 - 28% [95%CI 22 to 98%
34%]
References: [10, 18–20, 22, 23, 26–31, 33, 34, 41, 43, 45–50, 57, 58, 66, 71, 74, 77, 82, 84, 86–89, 93, 96, 98]
Mix ultrasound and chest 45 (38 to 50) 3 (30%) 50 8 (80%) 84 - 26% [95%CI 19 to 98%
X-ray 33%]
References: [25, 32, 36, 42, 44, 52, 53, 67, 70, 79]
Computed tomography 58 (58 to 58) 0 (0%) 62 2 (100%) 34 - 59% [95%CI 47 to -
71%]
References: [41, 76]
*P was calculated using Cuzick’s non-parametric test for trend [16]
CI = confidence interval, PE = pleural effusion

dengue is characterized by large plasma leakage, whereas associated with severe dengue [5], and the risk of hemor-
a small leakage does not have any clinical impact and rhagic fever increases with 8% for each year decrease in
may be more common than previously thought [4]. It is age [7]. Other reasons to account for this difference may
possible that the size of the effusion, or earlier detection be found in the underlying mechanisms of plasma leak-
of PE, could represent a better prognostic factor. This age. A proposed mechanism is dysfunction of endothelial
hypothesis was supported by Srikiatkhachorn et al, who glycocalyx [99]. This theory has emerged because leakage
demonstrated that the size of PE, assessed by ultrasound, often resolves suddenly, making endothelial apoptosis/
was directly associated with dengue severity (cross-sec- dysfunction less likely. The free NS1 and virus particles
tional width of PE in uncomplicated = 1 mm and compli- bind to the glycocalyx, which allows leakage of plasma
cated = 24 mm) [84]. Data on this was rarely reported in proteins such as albumin. The resulting fall in osmotic
the assessed studies and could thus not be analyzed, but pressure pulls plasma to the interstitial space and causes
future studies should delineate whether quantification of PE [99] (Supplemental Fig. 4). Furthermore, NS1 binds
PE by ultrasound offers additional clinical and/or prog- complement and causes release of vasoactive cytokines,
nostic value. increasing vascular permeability [100]. A smaller resis-
Fried et al [31] hypothesized that children have a tance to plasma leakage in children could be caused by
greater risk of PE, which is in line with the results in this age dependent endothelial differences. Young mammals
study (Table 1). A potential reason is that younger age is have a larger microvascular surface per unit volume of
Kaagaard et al. BMC Infectious Diseases (2023) 23:327 Page 6 of 9

skeletal muscle compared to adults, which means that qualitative vs. quantitative basis (i.e., volume cut-off ) and
endothelial dysfunction leads to more plasma leakage. if regional localization matters in dengue. Moreover, it is
Furthermore, microvessels in development have been of importance to elucidate if detection of PE in children
suggested to be more permeable to plasma [99]. A study offers enhanced opportunity for risk stratification and
by Gamble et al [101] examined vascular permeability in disease monitoring, considering children’s vulnerability
dengue patients and controls at different ages. Vascular to severe disease. Finally, there is a need to streamline the
permeability was three times higher in healthy children reporting of PE to reduce heterogeneity in observational
compared to young adults, and the value was approxi- studies of dengue.
mately 50% higher when infected with dengue. How-
ever, no difference in vascular function was observed in Limitations
those with and without shock, highlighting the need to We only included studies which reported on PE and this
improve our understanding of the pathophysiology of may lead to an overestimation of the real frequency. All
plasma leakage in children. Higher risk of severe infec- of our analyses displayed considerable heterogeneity
tion and frequency of PE in children may suggest that the as demonstrated by high I2 values, indicating high vari-
initial diagnostic workup in dengue should be age spe- ability in the reporting of PE. This could be due to dif-
cific, which is in contrast to the current guidelines from ferences in study design, included populations, reporting
WHO [3]. of outcome measures, disease severity and dengue clas-
Our findings indicate that ultrasound detects PE more sification algorithm. The high amount of heterogeneity
often than CXR (38% vs. 28%). A study by Prina et al may influence our results and render them less reliable.
[102] found that PE was detected in 93% of cases with Furthermore, several included studies lacked informa-
ultrasound and only in 47% when using CXR. Moreover, tion on age, severity and individual reporting of whether
other studies have shown that ultrasound may detect ultrasound or CXR had been used. Consequently, we had
smaller effusions (as low as ~ 20 mL), whereas effusions to include ‘mixed’ categories of age, severity and imag-
by CXR are visible when exceeding 200 mL [102]. In the ing method. In addition, a majority of studies did not
setting of dengue, ultrasound could prove useful as it is report on mortality and dengue serotype, thus not per-
faster compared to CXR, handheld devices may be used mitting us to examine if PE was linked to these param-
bedside in emergency departments and even non-physi- eters. PE is known to occur mostly during defervescence,
cian personnel can acquire and interpret lung ultrasound but many studies did not report timing for assessment.
images after brief training sessions [103]. This could ren- The few studies that measured PE at different time points
der it particularly useful for risk stratification in areas found significant differences between defervescence and
with few resources. Studies using CT had an even higher the febrile phase (Yousaf et al: 58% vs. 46%, Venkata et
frequency of PE, as would be expected since CT has a al: 72% vs. 6%). We defined our own categories of den-
very high sensitivity for such changes. However, it is also gue (complicated vs. uncomplicated) based on the 1997
more expensive and not practical to conduct CT scans and 2009 WHO classification instead of using one of the
on every dengue patient during an epidemic, thus poten- existing categories. This is not clinically optimal, but we
tially making ultrasound a more cost beneficial tool. deemed it necessary as we did not have access to indi-
Interestingly, the WHO classification algorithm (1997 vidual patient data. We found a significantly higher fre-
vs. 2009) was associated with PE such that studies using quency of PE in patients where the 1997 classification
the 1997 classification reported the highest frequencies was used, compared to those where the 2009 classifica-
of PE. Possible explanations are that diagnostics for PE tion was used. An important observation is that the 2009
have become more widespread and used at earlier and classification possibly is more sensitive and less specific,
milder stages of disease and a tendency towards a more leading to more patients classified with severe dengue
restricted fluid therapy in recent years. but without PE.
The results from this meta-analysis emphasizes that
although PE is a relatively common complication in den- Conclusion
gue, it varies according to severity, age and is influenced To our knowledge, this is the first meta-analysis to assess
by imaging modality. So far, classification of dengue the frequency of PE in dengue. We found that 33% of
severity is based on clinical evidence of fluid accumula- all dengue cases displayed PE, and this was significantly
tion. However, due to the high quality and low cost of higher in children (43%) and in patients with complicated
ultrasound for detecting PE, it is worthwhile to consider infection (48%). Furthermore, lung ultrasound more
if paraclinical evaluation could allow for a more precise often detected PE compared to CXR. Identification of
risk assessment. Future studies should aim to determine PE by lung ultrasound in dengue may represent a useful
if paraclinical assessment of PE is superior to that of tool to assess disease severity and risk stratify patients
clinical evaluation and whether it should be assessed on a
Kaagaard et al. BMC Infectious Diseases (2023) 23:327 Page 7 of 9

Author details
in remote environments without access to conventional 1
Multidisciplinary Center, Federal University of Acre, Campus Floresta,
imaging methods. Cruzeiro do Sul, Acre, Brazil
2
Cardiovascular Non-Invasive Imaging Research Laboratory, Department
List of Abbreviations of Cardiology, Herlev-Gentofte University Hospital, Hellerup, Denmark
3
CT Computed tomography Department of Bacteria, Parasites and Fungi, National Malaria Reference
CXR Chest X-ray Laboratory, Statens Serum Institut, Copenhagen, Denmark
4
ELISA Enzyme-Linked Immunosorbent Assay Health and Sport Science Center, Federal University of Acre, Rio Branco,
PE Pleural effusion Acre, Brazil
5
Foundation of Tropical Medicine Dr Heitor Vieira Dourado, Fiocruz,
Manaus, Brazil
6
Supplementary Information 7
University of Texas Medical Branch, Galveston, USA
The online version contains supplementary material available at https://doi. Laboratory of Host-Virus Interactions, Oswaldo Cruz Institute, Fiocruz, Rio
org/10.1186/s12879-023-08311-y. de Janeiro, RJ, Brazil
8
Faculty of Biomedical Sciences, Copenhagen University, Copenhagen,
Denmark
Supplementary Material 1 9
Sound Bioventures, Hellerup, Denmark

Acknowledgements Received: 17 February 2023 / Accepted: 6 May 2023

None.

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